Piperidinoethyl and piperidinoethoxyethyl esters of 2,2-diaryl-cyclopropane-carboxylic acids

ABSTRACT

The invention provides novel aminoethyl esters of 2,2diphenylcyclopropane carboxylic acids which are anti-tussive agents.

United States Patent Cognacq Nov. 5, 1974 PIPERIDINOETHYL AND PIPERIDINOETHOXYETHYL ESTERS OF 2,2-DlARYL-CYCLOPROPANE- CARBOXYLIC ACIDS Jean-Claude Cognacq, Bourg-la-Reine, France Inventor:

Assignee: Societe anonyme dite: Hexachimie,

Rueil-Malmaison, France Filed: Dec. 30, 1971 Appl. No.: 214,473

Foreign Application Priority Data Dec. 31, l970 Great Britain 62024/70 260/469, 247.2 B, 239 BF, 268 R [56] References Cited UNITED STATES PATENTS 3,317,526 5/1967 Dahlbom 260/469 OTHER PUBLICATIONS Hager et al., J. Am. Pharm. Assoc, 41: 193496, (1952). Weston, J.A.C.S., 68: 2345-2348, (1946). J. Pharmacol. & Exp. Therap, 96: 42, (I949), Kraatz et al.

Primary ExaminerJohn D. Randolph Assistant ExaminerS. D. Winters Attorney, Agent, or FirmArmstrong, Nikaido & Wegner [57] ABSTRACT The invention provides novel aminoethyl esters of 2,2-d iphenylcyclopropane carboxylic acids which are anti-tussive agents.

6 Claims, No Drawings PIPERIDINOETHYL AND R PIPERIDINOETHOXYETHYL ESTERS OF 2,2-DIARYL-CYCLOPROPANE-CARBOXYLIC (mule N ACIDS 1 5 Preseht invention P f estehs 0f 100 ml. of isopropanol and 0.21 mol of powdered sodlphehyl'eyelopropaheearhoxyhe aelds havlhg the dium hydroxide are added to a mixture of 0.1 mol of "111133 2,2-dipheny1-cyclopropane-carboxylic acid and 0.11 R molot piperidino-B-chloroethane hydrochloride. The

. /R C (-7 CH COOCHy-CH (O-CH CH N\ R a e (I) sium salt, of a 2,2-diphenyl-cyclopropane-carboxylic in which R is hydrogen, halogen, lower alkyl or lower mixture is heated under reflux for 8 hours, 300 ml. of

alkoxy, n is zero or 1, R and R together with the adjawater are added and the mixture extracted with diethyl cent nitrogen atom represent pyrrolidono, piperidino, ether. The ether phase is washed with water, dried over lower alkyl-substituted piperidino, morpholino, perhysodium sulphate, and the ether removed in vacuo to droazepino, piperazino, or N-(lower alkyl)piperazin0 yi the baSe- 1 and the pharmaceutically acceptable salts thereof. The preparaheh of the hydrochloride term lower alkyl denotes an alkyl radical having at A solution of hydrogen chloride in diethyl ether is most 4 carbon atoms added dropwise, with stirring, to a solution of the crude The invention also provides a process for the prepa base in 100 ml. of dlethyl ether, until the pH reaches ration of the compounds of formula I which comprises 1. The mixture is triturated, and the product crystallises reacting a metal salt, preferably the sodium or potas out. It IS filtered off, washed with diethyl ether, dried and recrystallised from isopropanol. The hydrochloride thus obtained, on rapid heating melts at 17880C;

acid with a compound of general formula: yield 78 percent- X'-CH CH OCH CH A N (II) Analysis C H CINHO N% calculated 3.63; i found 3.67.

in which X represents chlorine, bromine or iodine, and R R and n are as defined above. The reaction is car- 40 EXAMPLE 2 ried out in an alcoholic solvent, preferably ethanol or 2 (2I pyrro1idinb ethoxy)ethyl ester of 2,2 diphenyl isopropanol, at the boiling point of the said solvent. cyclopropane carboxylic acid Another process according to the present invention comprises reacting a 2,2-diphenyl-cyc1opropanecarboxylic acid chloride with an amino-alcohol of forl; mule: (Formula I, R H, n a 1, N I) ao-cn cn toea cn -a m (III) A solution of 0.1 mol of 2-(2'-pyrrolidinoi which R R d n are as d fi d b Th reacethoxy)ethanol in 30 ml. of anhydrous toluene is added tion can be carried out in an organic solvent such as didropwlse to mol of Sodium hydride in 20 ef ethyl ether, tetrahydrofuran, benzene, toluene, xylene, hydmhs teluehe- The mixture is allowed to 6001 and dimethylformamide or N-methyl-pyrrolid-2-on Th then stirred for 1 hour at ambient temperature. A soluamino-alcohol (III) may be converted intially into its P y y p p metal derivative, preferably into its sodium or potas- Farhoxyhe acid chlorlqe 30 of y e tehlehe sium derivative. If the amino-alcohol is not converted letheh added dropwlsewheh cool: the mixture 15 into its metal derivative, the reaction is carried out in for 2 hours at emblem temperature of the presence of a tertiary amine such as triethylamine. water are added e themlxture exhfacted Whh dlethyl The compounds according to the invention display ether. The extract is dr ed over sod um sulphate, and valuable pharmacological properties, in particular a the Solvent removed vacuo to Y' the basemarked anti-tussive action. preparaheh of the ehrate The following Examples illustrate the invention. A seluhoh of mol of e eh 250 of ethyl ether 15 added dropwise, with stirring, to 0.1 mol of citric acid in ml. of isopropanol. The mixture is EXAMPLE 1 stirred for 1 hour at ambient temperature and then trit- B-Piperidino-ethyl ester of 2,2-diphenyl-cyclopropaneurated. The product crystallises out, is filtered off, carboxylic acid washed with diethyl ether, dried, and recrystallised from isopropanol, to yield the citrate: ill-defined melting point at 102l08C; yield 70 percent.

Analysis C H NO N% calculated 2.45; 5

found 2.48.

EXAMPLE 3 BMorpholino-ethyl ester of 2,2-diphenyl-cyclopropane-carboxylic acid (Formula I, R H, n O,

A solution of 0.1 mol of 2,2-diphenyl-cyclopropanecarboxylic acid chloride in 30 ml. of anhydrous benzene is added dropwise to a mixture of 0.1 mol of B-morpholino-ethanol and 0.1 mol of triethylamine in 50 ml. of anhydrous benzene. The mixture is allowed to cool and then stirred for 2 hours at ambient temperature. 300 cc. of water was added, the mixture is extracted with diethyl ether, the extract dried over sodium sulphate, and the solvent removed in vacuo to yield the base.

Preparation of the hydrochloride A solution of hydrogen chloride in diethyl ether is added dropwise, with stirring, to a solution of crude base in 100 ml. of diethyl ether, until pH 1 is reached. The mixture is triturated, and the product crystallises; it is filtered off, washed with diethyl ether and recryslnllised from isopropzmol to yield the hydrochloride: melting point l5l)"-l52"(; yield 7o percent.

Analysis (,-,H-,.,(IN();.. NYn calculated 3m; l'ound 3.62.

Other compounds having the general formula I were also prepared by the procedures described in the above Examples; these compounds are listed in Table l below.

The pharmacological properties of the esters of 2,2- diphenyl-cyclopropane-carboxylic acid and of their addition salts with non-toxic acids are demonstrated in the following tests, which were carried out on SPF rats and mice, on guinea pigs and on cats.

The products tested are dissolved in a 9% sodium chloride solution or, if they are insoluble in this solution, suspended using Tween (for oral and intraperitoneal administration) or dissolved in polyethylene glycol 300 (for intravenous administration).

The volumes administered are Rat l ml./kg. Mouse 0.5 ml./20 g. Guinea Pig 1 ml./kg. Cat 1 mlJkg.

1. Acute toxicity The acute toxicity is determined on batches, each of two rats. The doses administered extend from 4 to 512 mg./kg. in geometrical progression, constant ratio 2.

Table II below gives the 0 and (percent) lethal doses, 2 days after treatment, in mg./kg. administered intraperitoneally.

2. Anti-tussive activity: Domenjoz method Cats are anaesthetised by intraperitoneal injection of 30 mg./kg. of sodium mebubarbital. The arterial pres- TABLE l 4 Annlysls for N Formula I N Melting (percent) Example Method of Yield, (.rystelllsutlen pelnl. No. it: n working percent lJerlvntlve solvent Cnled. Found Example 1. 63 lyrrolidlno 0 Example 2.. 70 1Iydroch1orlde.... Isopropanol 164-5 3.77 3.76

Example 3. 78 Example 1.. 78 Piperidlno 0 Example 2.- 77 d0 "do 178-80 3.63 3.67

Example 3.. 79 Example 1.. 50 Ierhydreezeplno 0 Example 2.. 63 .do Ethanol 200-2 3.50 3.49

Example 3.. 75 Example 1- 62 Mornhollno 0 Exmnpleh. 74 ...do Methyl ethyl ketone -2 3.61 3. 62

Exiunple 3 76 Example 1. 57 N-methylplnemzlno 0 Exmn le2. 76 Dihydroehlerlde. Ethanol 202 6.36 6.36

Exmnple 3. 74 3'-mothylplperldlno... 0 Exemple3. 65 100 3.50 3.40 4-methyl lpeildlno... 0 lo 77 162 3.50 3. 55 26'-dlmet iyl- 0 ...do 45 ....do ..de 184 3. 38 3.20

plperldlno. 12 p-Clla Pyrrolldlno 0.....(10 58 Mnlonto lsnmprienolnthyl 102 2.02 2.80

600 n o. l3.v p-Ulln llperldlno 0 ....do 68 ltthylncetnte................. 131 2.83 2.8 MM... n-(ll ....do..... ll .....(lo.. 6h llyrlrrmhlorldon lsoprrmnnet. 168 3.08 3.20 If. p-(Jlln lo... (I .imdoI lxbnht llvlntlmnol..i H0373 'lXltllI|)l!'-..... .1 m o soni'opnnn I) Il ly n K 1 lllilxlllllllrllg... oxmntn l() 1:44 2.0x 2.87 I lxmnno. I t 1 l1 ll Illmlldlno... l g st (.llnntn" do. 106 ll) 2.. ...dl. H ll lm'hydrollzeplno l llydroohlol'lde Ethyl nnnlnto Ht! 3. lo 3.15

lll... ll N-lnethylplpornzlno.. 1 l)lhydroehlerldo... lsopropnnnl 170 6.82 5 76 *lnsty melting.

sure is measured on the femoral artery by a Statham P 23 Db gauge. A tracheotomy is carried out; a Y-shaped cannula allows a part of the air breathed out to be branched off onto a Statham PM 6 gauge; the cardiac rhythm is measured by integration of the QRS complexes of the electrocardiogram. All these measurements are amplified and recorded on a Beckman Dynograph. The two upper laryngeal nerves are very carefully dissected and stimulated for 10 seconds by a surging current generated by a Hugo Sachs Stimulator I: voltage 3 volts, duration 50 minutes, frequency 50 cycles/second. The test products are injected into the femoral vein. The first stimulation takes place 5 minutes after administration of the product and then every 5 minutes until the reaction returns to the initial amplitude. Each nerve is stimulated in turn (left-hand nerve: 5, 15, 25 minutes etc; right-hand nerve 10, 30, 40 minutes etc. after treatment).

The intravenous administration of 1 to 2 mg./kg. of

codeine phosphate reversibly inhibits the reaction to the stimulation.

Table III below shows the activity of the products, defined as follows:

inactive marked diminution of cough +1- suppression of cough for to 15 minutes -H-+ suppression of cough for more than 15 minutes TABLE III Compound of Example No. Rating l and 5 +-H- 2 and 16 3 and 7 4 -H- 6 -H- 8 9 +1- 10 11 -H- 12 -H- 13 14 15 17 -H- 18 19 4. Local anaesthetic activity This is investigated by the technique of Bulbring and Wajda. The backs of male guinea pigs weighing 350-450 g. are shaved with an electric razor. 0.1 ml. of a solution of the compounds to be tested is injected into the dermis (only those products which are soluble in the sodium chloride solution and give a pH of 6 to 7 are examined). Four points spaced 2 cm apart are marked on the skin, the product being administered at two of these and the solvent being administered at the remaining two. The skin reflex is examined by pricking each point six times with a mounted bristle. The number of positive reactions is'counted and an inhibition percentage is calculated from the total number of positive reactions over the course of minutes. Table V gives the inhibition percentages measured as a function of the concentrations of the solutions. The compounds of Examples 6, l7 and 18 are insoluble under the experimental conditions.

Example 19 Clinical experiments were also carried out with the product of Example 1 on subjects suffering from chronic bronchitis. Not only suppression of the cough, but also facilitation of espectoration, and even a reduction in the latter and a sensation of feeling better, were observed.

The compounds of formula I can be administered orally at a dose of to 600 mg. daily. Formulation for gelatine-coated pills Gelatine-coated pills containing 50 mg. of the compound of Example 1, to be administered at the rate of 1 to 6 gelatine-coated pills daily, taken in 1 to 3 doses.

Formulation of a syrup Compound of Example 1 mg. Flavoured syrup 100 m in l to 3 doses. Formulation for suppositories TABLE IV Compound of Example No. Dose. mg/kg 1 2 3 administered and and and 4 6 8 9 10 l 1 12 13 14 15 17 18 19 orally 5 16 7 16 l 10 57 25 14 21 22 45 24 35 29 40 43 3 26 32 38 37 0 64 31 63 25 19 46 38 36 24 38 29 28 55 26 38 I28 41 I9 Compound of Example I Cacao butter. q.s.p.

to be administered at the rate of l to 3 suppositories dail The invention thus includes within its scope pharmaceutical compositions comprising, in association with a compatible pharmaceutical carrier, at least one compound of formula I or non-toxic acid addition salt thereof, preferably in a form for oral administration such as a tablet, sugar-coated pill, gelatine-coated pill,

or syrup.

I claim:

1. An ester of a 2,2-diphenyl cyclopropanecarboxylic acid having the formula:

CH-COOCH -CH (O-CH CH -N in which R is hydrogen, halogen, lower alkyl, or lower 2 alkoxy, n is zero or 1, and R and R together with the nitrogen atom to which they are attached, form piperidino or lower alkyl-substituted piperidino or a pharmaceutically acceptable salt thereof.

tion salt thereof.

6. The ester according to claim 1 which is the 2-(2'- piperidino-ethoxy )-ethyl ester of 2 ,2-di-( pmethylphenyl)-cyclopropanecarboxylic acid or a nontoxic acid addition salt thereof. 

1. AN ESTER OF A 2,2-DIPHENYL CYCLOPROPANE-CARBOXYLIC ACID HAVING THE FORMULA:
 2. The ester according to claim 1 which is the Beta -piperidinoethyl ester of 2,2-diphenyl-cyclopropane-carboxylic acid or a non-toxic acid addition salt thereof.
 3. The ester according to claim 1 which is the Beta -(4''-methyl-piperidino)ethyl ester of 2,2-diphenylcyclopropanecarboxylic acid or a non-toxic acid addition salt thereof.
 4. The ester according to claim 1 which is the Beta -(2'',6''-dImethyl-piperidino)ethyl ester of 2,2-diphenylcyclopropanecarboxylic acid or a non-toxic acid addition salt thereof.
 5. The ester according to claim 1 which is the Beta -piperidinoethyl ester of 2,2-di-(p-methyl-phenyl)-cyclopropanecarboxylic acid or a non-toxic acid addition salt thereof.
 6. The ester according to claim 1 which is the 2-(2''-piperidino-ethoxy)-ethyl ester of 2,2-di-(p-methylphenyl)-cyclopropanecarboxylic acid or a non-toxic acid addition salt thereof. 